Calcification in original plaque and restenosis following carotid artery stenting

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1 SNI: Neurovsculr OPEN ACCESS For entire Editoril Bord visit : Editor: Kzuhiro Hongo, M.D., Shinsui University, Mtsomoto, Jpn Originl Article Clcifiction in originl plque nd restenosis following crotid rtery stenting Hiroyuki Ktno 1,2, Yusuke Nishikw 1, Hiroshi Ymd 1, Mitsuhito Mse 1 Deprtments of 1 Neurosurgery, 2 Medicl informtics nd Integrtive Medicine, Ngoy City University Grdute School of Medicl Sciences, 1 Kwsumi, Mizuho cho, Mizuho ku, Ngoy , Jpn E mil: *Hiroyuki Ktno ktno@med.ngoy cu.c.jp; Yusuke Nishikw yusuken@med.ngoy cu.c.jp; Hiroshi Ymd hymd@med.ngoy cu.c.jp; Mitsuhito Mse mitmse@med.ngoy cu.c.jp *Corresponding uthor Received: 18 July 17 Accepted: 13 September 17 Published: 20 November 17 Abstrct Bckground: The reltionship between clcifiction in primry plque nd recurrent stenosis fter crotid rtery stenting (CAS) is not estblished, but n inverse ssocition with restenosis following crotid endrterectomy (CEA) hs been suggested. Methods: We retrospectively nlyzed 75 plques of 109 consecutive CAS with regrd to clcifiction, using the clcium score nd shpe, loction, nd other chrcteristics of originl plques together with stenting relted fctors. CAS ws performed in stndrd fshion with n embolic protection device. Greter thn moderte restenosis ( 50%) ws ssessed by pek systolic velocity (PSV) with duplex ultrsonogrphy ( 130 cm/s, internl/common crotid or distl/proximl PSV rtio 2.0). Results: Univrite nlysis reveled percentges of dyslipidemi treted with sttins (P = 0.03), clcifiction in distl ICA (P = 0.02), nd immedite residul stenosis (P = 0.02) were significntly higher in ptients with greter thn moderte restenosis, wheres clcifiction in crotid bulb nd usge of open cell stent were rther less frequent (P < nd P = 0.02, respectively). Multivrite logistic regression nlysis showed tht rrity of clcifiction in crotid bulb ws sole independent predictor for greter thn moderte recurrent crotid stenosis 1 yer fter CAS (OR = 0.21, CI = , P = 0.02). Conclusions: Clcium score ws not significntly relted to restenosis t 1 yer fter CAS, s ws previously found following CEA, though scrcity of clcifiction in crotid bulb ws suggested s predictor of in stent restenosis. Compred to post CEA restenosis, crotid plque clcifiction my be inversely but tenuously ssocited with recurrent stenosis 1 yer post CAS. No other stenting fctors (e.g., stent design, pre /post diltion, or protection devices) showed significnt ssocition with recurrent stenosis post CAS. Access this rticle online Website: DOI: /sni.sni_263_17 Quick Response Code: This is n open ccess rticle distributed under the terms of the Cretive Commons Attribution NonCommercil ShreAlike 3.0 License, which llows others to remix, twek, nd build upon the work non commercilly, s long s the uthor is credited nd the new cretions re licensed under the identicl terms. For reprints contct: reprints@medknow.com How to cite this rticle: Ktno H, Nishikw Y, Ymd H, Mse M. Clcifiction in originl plque nd restenosis following crotid rtery stenting. Surg Neurol Int 2017;8: Surgicl Neurology Interntionl Published by Wolters Kluwer - Medknow

2 Key Words: Clcifiction, clcium score, crotid rtery stenting, crotid stenosis, in stent restenosis INTRODUCTION Recurrent stenosis or in stent restenosis fter crotid rtery stenting (CAS) is known s risk fctor of ipsilterl stroke, nd this stroke risk should be monitored during ptient follow up. [22 24] Severl fctors relted to post CAS restenosis hve been reported, including demogrphy, comorbidity, nd/or chrcters of originl plques, e.g., ge, [4,22] femle gender, [22] symptomtic cses, [13] dibetes, [5,22] hypertension, [22,40] hyperlipidemi, [22] inflmmtion mrkers, [37] high degree stenosis, [32] nd length of the plques, [31] lthough some of these studies merely conducted univrite or combined nlyses with restenoses fter crotid endrterectomy (CEA). Severl reserchers reported CAS procedure relted fctors of post CAS restenosis, such s immedite residul stenosis, [7,31,40] double stent deployment, [7] use of n open cell stent, [20] nd the prediltion blloon dimeter. [32] A recent reserch clrified tht greter thn moderte recurrent stenosis fter CEA ws less frequent in crotid plques with higher clcium scores, indicting tht plque clcifiction is inversely relted to post CEA restenosis. [15] However, the mechnism of restenosis tht occurs within few yers fter CAS is thought to be due to myointiml hyperplsi, s in CEA, wheres the mechnism of lter post CAS stenosis is thought to be due to therosclerosis. [7] If the post CAS etiology is similr to tht of post CEA restenosis in the erly period, it is conceivble tht there is n nlogous ssocition between clcifiction in crotid plque nd recurrent stenosis; however, the reltionship between plque clcifiction nd restenosis fter CAS hs not been thoroughly investigted. We conducted the present study to evlute the clcifiction in originl plque using the clcium score s well s the shpe nd loction of the plque, nd to elucidte the involvement of these nd other fctors in the recurrence of stenosis fter CAS. PATIENTS AND METHODS Ptient popultion nd surgicl tretments The smple included totl of 109 consecutive cses of CAS performed between Februry 2005 nd December Fifteen ptients with follow up periods <1 yer, seven ptients with secondry stenting, 11 ptients with missing pek systolic velocity (PSV) dt of duplex ultrsonogrphy (DUS) t 1 yer, nd two ptients without computed tomogrphy ngiogrphy (CTA) dt for renl filure were excluded from the study. A finl totl of 75 crotid rteries with CAS including two bilterl stentings nd four post CEA cses were enrolled in the study nd retrospectively nlyzed. The men follow up period ws 43.3 ± 29.5 months. No trnsient or permnent focl neurologic symptoms of the contrlterl limbs or ipsilterl retin were observed in the ptients with postopertive recurrent stenosis. The ptient dt re summrized in Tble 1. Surgicl indictions for the tretment of crotid stenosis dhered to the criteri of the North Americn Symptomtic Crotid Endrterectomy Tril (NASCET), [6] the Asymptomtic Crotid Atherosclerosis Study (ACAS), [1] nd the Stenting nd Angioplsty with Protection in Ptients t High Risk for Endrterectomy (SAPPHIRE) Tble 1: Chrcteristics of cses strtified ccording to degree of stenosis t 1 yer Degree of restenosis t 1 yer post opertion (%) Totl 0 stenosis <50 50 stenosis * P n Age (yr/o) 73.8± ± ± Mle sex (%) b Degree of originl crotid stenosis (%) 77.7± ± ± Symptomtic cse (%) b Follow up period (dy) ± ± ± Antihypertensive use (%) b Hypoglycemic drug use (%) b Sttin use (%) b Ischemic hert disese with PCI (%) b Renl mlfunction (%) b Smoking history (%) b Antipltelet use (%) b Anticogulnt use (%) b Mnn Whitney U test, b Chi squre nlysis. PCI: Percutneous coronry intervention, * PSV: Pek systolic velocity 130 cm/sec, internl/crotid rtery or distl/proximl PSV rtio 2.0

3 study. [38] The surgicl methods nd selection of CAS nd CEA were s described. [17,19] CAS ws performed using Wllstent in 44 of the 75 cses (58.7%) (Boston Scientific, Freemont, CA) nd PRECISE stent in the other 31 cses (41.3%) (Cordis, Bridgewter, NJ,) with or without prediltion (6 tm, 30 s, Sterling, Boston Scientific) nd postdiltion (10 tm, s, Avitor, Cordis). A filter (Angiogurd XP, Cordis), distl blloon (PercuSurge Gurdwire, Medtronic, Snt Ros, CA), nd/or flow reversl (Ptlive, Terumo Clinicl Supply, Kkmighr, Jpn) embolic protection devices were used. The use of pre /postdiltion nd the selection of the types of stents nd protection devices were determined t the discretion of the interventionlists. Dul ntipltelet therpy (DAPT) using minly spirin (100 mg/dy)/ clopidogrel (75 mg/dy) or cilostzol (200 mg/dy) were performed (except in six cses with clopidogrel/ cilostzol combintion nd two with triple ntipltelet therpy) t 5 dys before CAS nd were continued fter the procedure for 3 months; nd lifetime continution of solely spirin ws prescribed. The ptients use(s) of ntihypertensives, hypoglycemic drugs, sttins, ntipltelets, nd nticogulnts were checked. Renl mlfunction ws defined s serum cretinine >1.5 mg/dl nd/or blood ure nitrogen (BUN) >30 mg/dl. History of smoking ws defined s ptient who hd pttern of >100 cigrettes/lifetime in the pst nd/or t the time of recording. The study design ws pproved by the locl ethics committee, nd the ethicl guidelines for medicl nd helth reserch involving humn prticipnts issued by the Jpnese Helth Lbor nd Welfre Ministry (2014) were strictly observed. Assessment of the clcium score of the plques with multidetector row computed tomogphy Multidetector row CT (MDCT) ngiogrphy ws performed preopertively in ll enrolled ptients with 64 detector row CT scnner (SOMATOM Definition: Siemens Medicl Solutions, Forchheim, Germny) or 16 detector row CT scnner (IDT 16: Philips Medicl Systems, Best, Netherlnds). [17,18] The imging cquisition prmeters were s follows: spirl mode 0.33 s gntry rottion; collimtion, mm; pitch fctor, 1.5; section thickness 1.0 mm; reconstruction intervl, 0.5 mm, nd cquisition prmeters 120 kvp nd 350 ma. A totl of 50 ml of nonionized contrst medium [either iohexol (Omnipque 300; Diichi Snkyo, Tokyo) or iopmidol (Iopmiron 300; Byer Schering Phrm, Berlin, Germny)] ws injected t flow rte of 3.5 ml/s, followed by 25 ml sline chser t the sme rte s the contrst medium. The optiml timing of MDCT ngiogrphy cquisition ws determined by n utomted bolus timing progrm. Imges were obtined from the ortic rch to the level of the inferior orbits. The imge dt were trnsferred to computer worksttion (Ziosttion version 1.17; Amin, Tokyo) for imge postprocessing, nd the clcifiction of the crotid plque ws preopertively quntified. The Agtston clcium score [3] of ny clcifiction re >1 mm 2 with ttenution 130 Hounsfield units (HU) ws determined by multiplying the lesion re (totl number of pixels) by the cofctor 1 4 (cofctor 1, HU; cofctor 2, HU; cofctor 3, HU; cofctor 4, 400 HU) with noncontrst enhnced CT obtined before the contrst medi injection for CT ngiogrphy. Clcium ws further quntified in cubic millimeters with the volume score clculted s the product of the voxel volume nd the number of voxels in the region of interest; the overll clcium score of the plque ws the sum of the vlues for ll individul lesions by computer ssisted utomtic mesurement. Assessment of the clcifiction in crotid plque, positive remodeling, nd stenosis Assessment of plque clcifiction chrcteristics ws preopertively performed s described. [16] The shpe of the clcifiction in the crotid plque ws strtified nd scored with enhnced MDCT ccording to circulrity, or the degree to which the plque encircled the vessel perimeter: 1, less thn one qurter; 2, one qurter to one hlf; 3, more thn one hlf up to three qurters; 4, more thn three qurters up to less thn full circle; nd 5, full circle covering the entire crotid perimeter. We clssified nd scored the inner (intiml) nd outer (dventitil) position of the clcifiction in the crotid plque in the crotid wll bsed on enhnced CT: 1, inner side in the crotid wll only; 2, inner >outer, 3: inner = outer, 4: inner <outer, 5: outer side in the crotid wll only. The loction of plque clcifiction ws ssessed in terms of whether clcifiction existed in the common crotid rtery (CCA), the bulb, nd/or the distl prt of the internl crotid rtery (ICA), llowing multiple registries. We determined the degree of pthologicl findings other thn clcifiction bsed on histopthologicl specimens of the extrcted plques stined with hemtoxylin eosin just fter the opertion nd scored s follows: lipid core (0: none, 1: smll, 2: medium, 3: lrge), fibrous tissue (0: none, 1: thin, 2: thick), nd intrplque hemorrhge (0: none, 1: slight, 2: prominent). Positive remodeling ws defined s remodeling rtio (RR) >1.1, where RR = the cross sectionl dimeter (CSD) t the point of mximum stenosis in the (ICA)/the reference CSD t the distl ICA. [28] The height of the distl end of the crotid plque ws divided when it existed beyond the level over C2. The loction of the restenosis ws evluted with respect to whether

4 stenosis existed in the proximl CCA, the CCA to crotid bulb, nd the ICA to the crotid bulb nd/or distl ICA, llowing multiple registries. Assessment of the stenting relted fctors The stent types (open /closed cell), implementtion of pre diltion/post diltion, nd protection for emboliztion (distl/proximl) were checked nd evluted. Crotid tortuosity ws defined s crotid curvture of the stenting site <120, nd difficult distl lnding zone ws determined s severe ngultion or tortuosity for protective embolic devices, ccording to the Bufflo risk ssessment scle (BRASS). [11] Duplex ultrsonogrphy The degree of restenosis fter CAS ws ssessed by PSV on high resolution ultrsonogrphy, with liner trnsducer t 7.5 MHz in the B mode (Aplio, Toshib Medicl Systems, Otwr, Jpn). The highest PSV from the treted ICA or CCA ws used to identify restenosis. The PSV threshold for predicting 50% crotid stenosis ws 130 cm/s bsed on recent precise study [35] plus PSV rtio 2.0 for the ICA to the CCA or the distl to proximl portion of the stenosis. The miniml dimeters of the greter thn moderte restenoses ( 50%) were ll 3.0 mm. Sttisticl nlysis All sttisticl evlutions were performed with Sttview ver. 5.0 softwre (SAS, Cry, NC) nd SttMte III (ATMS, Tokyo), nd ll results re presented s men ± SD vlues. The Chi squre test with Ytes correction nd the Mnn Whitney U test were used for comprisons. For the multivrite nlysis, binry logistic regression model ws used. Probbility (P) vlues <0.05 were considered significnt. RESULTS Bseline chrcteristics There were no significnt differences in bsic dt concerning ge, gender, degree of originl crotid stenosis or follow up period between the groups with no or mild stenosis (<50%; n = 55) nd greter thn moderte restenosis ( 50%; n = 20) groups t 1 yer postopertion [Tble 1]. The percentge of ptients with dyslipidemi treted with sttin ws significntly higher in the greter thn moderte restenosis group t 85% compred to the no or mild stenosis group t 72.7% (P = 0.03). The use of ntihypertensives or severl other importnt drugs nd smoking hbit were not significntly different between the two groups. Originl plque chrcteristics nd fctors for stenting We performed univrite nlysis for the bove two groups regrding originl plque chrcteristics. No significnt difference ws found for the length, height of the distl end, positive remodeling, or loction of the initil stenosis [Tble 2]. Regrding clcifiction in the crotid plques, in the greter thn moderte restenosis group, clcifiction s existence ws significntly less frequent in the crotid bulb but significntly more frequent in the distl ICA compred to the other group (P < nd P = 0.02, respectively). There were no significnt differences in Tble 2: Chrcteristics of plque nd stenosis strtified ccording to degree of stenosis t 1 yer Degree of restenosis t 1 yer post opertion (%) Totl 0 stenosis <50 50 stenosis * P Originl plque length (mm) 24.0± ± ± Originl plque distl end: C2 or upper (%) b Originl plque (stenosis) loction b CCA bulb (%) ICA bulb (%) Distl ICA (%) Positive remodeling (%) b Mnn Whitney U-test, b Chi squre nlysis. CCA: Common crotid rtery, ICA: Internl crotid rtery. * PSV: Pek systolic velocity 130 cm/sec, internl/crotid rtery or distl/ proximl PSV rtio 2.0 Tble 3: Chrcteristics of plque nd stenosis strtified ccording to degree of stenosis t 1 yer (regrding clcifiction) Degree of restenosis t 1 yer post opertion (%) Totl 0 stenosis <50 50 stenosis * P Clcium score 314.0± ± ± Clcifiction shpe score (circulrity) 1.5± ± ± Clcifiction position score (inside/outside) 2.3± ± ± Clcifiction loction b CCA (%) Crotid bulb (%) <0.001 Distl ICA (%) Mnn Whitney U test, b Chi squre nlysis. * PSV: Pek systolic velocity 130 cm/sec, internl/crotid rtery or distl/proximl PSV rtio 2.0

5 clcium score, clcium shpe score (circulrity), or position score (inside/outside) between the two groups [Tble 3]. Concerning the stenting relted fctors, the use of n open cell stent ws significntly less frequent in the greter thn moderte restenosis group, wheres immedite residul stenosis ws significntly higher (both P = 0.02) by univrite nlysis. No significnt differences between the no or mild nd greter thn moderte restenosis groups were reveled concerning pre nd post diltion, the use of proximl emboliztion protection, crotid tortuosity, nd difficult distl lnding zone [Tble 4]. The results of the multivrite logistic regression nlysis indicted tht scrce clcifiction in the crotid bulb ws the only significnt independent predictor of post CAS greter thn moderte restenosis t 1 yer (OR = 0.21, CI = , P = 0.02) [Tble 5]. The pictures of representtive cses re shown in Figures 1 4. Tble 4: Stenting-relted fctors strtified ccording to degree of stenosis t 1 yer Degree of restenosis t 1 yer post opertion (%) Totl 0 stenosis <50 50 stenosis * P Open cell stent (%) Pre diltion (%) Post diltion (%) Proximl emboliztion protection (%) Crotid tortuosity (%) Difficult distl lnding zone b (%) Immedite residul stenosis (%) Chi squre nlyses. * PSV: Pek systolic velocity 130 cm/sec, internl/crotid rtery or distl/proximl PSV rtio 2.0. Crotid curvture of the stenting site <120. b Severe ngultion/tortuosity for protective embolic devices b c d e Figure 1: A 84 yer old mle with right symptomtic crotid stenosis. Volume rendering (), mximum intensity projection (b), imges of multidetector row CT nd digitl subtrction ngiogrphy (c), before crotid rtery stenting (CAS). Clcifiction ws observed in the crotid bulb nd the common crotid rtery. (d) The Wllstent ws successfully plced immeditely fter the procedure. (e) Duplex ultrsonogrphy one yer fter CAS reveled tht the pek systolic velocity ws 63.8 cm/s b c d e f Figure 2: A 81 yer old mle with right symptomtic crotid stenosis. Volume rendering (, b) mximum intensity projection (c), imges of multidetector row CT, nd digitl subtrction ngiogrphy (d) before crotid rtery stenting (CAS). Clcifiction ws observed in the crotid bulb, the common nd distl internl crotid rtery. (e) The Wllstent ws successfully plced immeditely fter the procedure. (f) Duplex ultrsonogrphy one yer fter CAS reveled tht the pek systolic velocity ws 91.5 cm/s

6 b c d e Figure 3: A 73 yer old mle with right symptomtic crotid stenosis. Volume rendering (), mximum intensity projection (b), imges of multidetector row CT nd digitl subtrction ngiogrphy (c), before crotid rtery stenting (CAS). Clcifiction ws observed in the common nd the distl internl crotid rtery. (d) The Wllstent ws successfully plced immeditely fter the procedure. (e) Duplex ultrsonogrphy one yer fter CAS reveled tht the pek systolic velocity (PSV) ws cm/s nd the PSV rtio for the distl to the proximl portion of the stenosis ws 2.0 b c d e Figure 4: A 65 yer old mle with left symptomtic crotid stenosis. Volume rendering (), mximum intensity projection (b), imges of multidetector row CT nd digitl subtrction ngiogrphy (c), before crotid rtery stenting (CAS). Clcifiction ws observed only in the common crotid rtery. (d) The Wllstent ws successfully plced immeditely fter the procedure. (e) Duplex ultrsonogrphy one yer fter CAS reveled tht the pek systolic velocity ws cm/s nd the PSV rtio for the distl to the proximl portion of the stenosis ws 6.1 Tble 5: Multivrite logistic regression nlysis of greter thn moderte postopertive restenosis t 1 yer * DISCUSSION Odds rtio 95% CI P Age (<71) Femle sex Treted dyslipidemi Clcifiction on crotid bulb Clcifiction on distl ICA , Open cell stent Immedite residul stenosis (>50%) * PSV: Pek systolic velocity 130 cm/sec, internl/crotid rtery or distl/proximl PSV rtio 2.0 Our study s multivrite regression nlysis reveled tht scrcity of clcifiction in the crotid bulb ws the sole independent predictor of greter thn moderte recurrent stenosis fter CAS. The clcium score nd the clcifiction circulrity, which hve been reported to be predictors of restenosis in CEA, [15] were not significnt in the reltionship between clcifiction nd post CAS restenosis in the present study. Comprison of the present nd previous findings regrding restenosis fter CAS Prior investigtions of restenosis fter CAS showed severl importnt nd relted fctors concerning demogrphics nd comorbidity. As lrge study, subnlysis of the CREST tril [22] reveled tht femle gender, dibetes, nd dyslipidemi were independent predictors of restenosis or occlusion fter CEA nd CAS. A subnlysis of the EVA 3S study [4] showed tht restenosis ( 50%) or occlusion ws significntly higher fter CAS thn fter CEA, nd tht the ptient s ge t bseline ws the only vsculr risk fctor. Recent studies described dibetes, [5,30] history of cerebrovsculr disese, nd hving cerebrovsculr ccident prior to stenting, [9] smoking, symptomtic stenosis, nd de novo stenosis [30] s predictors of in stent recurrent stenosis. Zpt Arriz et l. [40] reported tht hypertension nd impired vsorectivity were independent risk predictors of restenosis ( 70%), though their cohort included

7 only ngioplsty cses without stents. Regrding chrcteristics of the originl plque, plques longer thn 20 mm were reported to be significntly relted to restenosis. [31] In our present study, we found no significnt difference between the no or mild restenosis nd greter thn moderte restenosis groups concerning demogrphics, concomitnt conditions, nd chrcteristics of the originl plque nd stenosis [Tbles 1 nd 2] except for sttin use. Some experimentl reports described tht sttins were effective for countercting restenosis, but this hs not been confirmed. [14,33] AbuRhm et l. reported tht sttins hd no effect on preventing post CEA restenosis, lthough sttins lowered the postopertive deth nd stroke rtes in dibetic ptients. [2] Regrding the usge of ntipltelets, severl reports indicted therpeutic effect of cilostzol. [26,34,39] In the present study, the rte of prescriptions of cilostzol showed no significnt difference between the no or mild restenosis nd greter thn moderte stenosis groups: 52.7% (29/55) vs. 50.0% (10/20), respectively. Reltionship between restenosis nd fctors relted to CAS Regrding the fctors relted to stent mterils, procedures, nd the postopertive stte, the reported independent predictors of restenosis re immedite post CAS residul stenosis, [7,31] stent length nd width, [37] nd double stent deployment. [7] Plque protrusion hs been reported to be observed frequently in open cell stent use compred to closed cell stents, [20] but de Donto et l. [10] demonstrted tht stent chrcteristics (mteril/ design/free cell re) were not significntly ssocited with in stent restenosis in 5 yer follow up. Okhr et l. lso showed no difference in plque protrusion between open nd closed cell stents. [29] In our study, though the multivrite nlysis reveled no significnce, the results of the univrite nlysis regrding immedite residul stenosis ws in ccordnce with previous reports, [7,31] lthough open cell stent use ws rther less frequent in the present greter thn moderte restenosis group. This might be relted to the vritions mong the studies regrding the definition of restenosis nd the modlities used to ssess the degree of restenosis nd its definition, especilly the estimted degree of stenosis nd the corresponding PSV in DUS s ws suggested. [8] The discordnt findings might lso hve been ffected by the limited number of smples in the present study. Clcifiction in crotid plques nd restenosis fter CAS Concerning clcifiction in originl plque, Moon et l. [27] reported tht clcifiction might be predictor of restenosis ( 50%), though their follow up period vried from 1 to 204 months. In ddition, they did not describe how they evluted clcifiction nd wht type of stents they used. Ronchey et l. [30] showed tht clcifiction ws ssocited with restenosis s well s other fctors bsed on their nlysis of 1,000 cses of CAS using Wllstents. Although they defined plques with Gry Wele clssifictions III/IV [12] s clcified plques, those clsses ctully contined fibrous plques s echogenic crotid plques. On the other hnd, Wsser et l. [36] speculted tht the risk of intim injury (which is suspected to be the initil trigger of restenosis) ws lower in clcified plques compred to soft vulnerble plques. Miski et l. [25] recently reported tht high volume of plque components with rdiodensities <0 HU ws independently ssocited with the incresed risk of restenosis fter CAS. Here, we used clcium score tht ws n integrted indictor encompssing hrdness nd volume. We lso precisely evluted the clcifiction, i.e., its shpe, position, nd loction. However, scrcity of clcifiction in the crotid bulb ws the sole independent predictor by multivrite nlysis. The incidence of the greter thn moderte restenosis tht occurred in the re concerning the crotid bulb for plques without clcifiction (9/11; 81.8%) ws greter thn tht for plques with clcifiction in the sme re (33.3%; 3/9). This suggests tht clcifiction ws inversely ssocited with restenosis, which is in line with the findings reported by Miski et l. A previous nlysis concerning restenosis fter CEA reveled n pprent inverse reltionship with clcium score nd the circulrity of clcifiction, [15] nd our present results demonstrted tht in stent restenosis following CAS ws lso inversely but tenuously ssocited with clcifiction in crotid plques compred to tht in CEA. The reson for this modest ssocition is obscure, but it might be scribed to multiple complex fctors nd their interctions such s plque protrusion/thrombus, stent mterils, nd stenting techniques (which would not be expected to be ssocited with CEA) though they my not hve intimte involvement in restenosis individully. Limittions The primry limittions of our study re its retrospective chrcter nd the smll number of cses. We used DUS for the ssessment of the degree of in stent restenosis, wheres the use of PSV to estimte the degree of stenosis vries mong reserchers. [8,35] Though DUS ws voided nd CTA ws used for the study of restenosis fter CEA, [15] CTA ws reported to overestimte the percent stenosis for bem hrdening rtifcts nd ws inferior to DUS in determining in stent restenosis. [21] We used DUS in the present study, but it is possible tht our study included cses of milder restenosis thn those exmined

8 in other studies, lthough we pplied the criteri from recent meticulous study. [8,35] CONCLUSIONS Scrcity of clcifiction in the crotid bulb ws the sole predictor of in stent restenosis 1 yer fter CAS, nd the clcium score ws not significntly ssocited with recurrence, s ws observed following CEA. The reltionship between crotid clcifiction nd recurrent stenosis 1 yer fter CAS might be reverse, but it my be more tenuous thn tht fter CEA. Acknowledgments We thnk ll of our wrd stff for their invluble clinicl contributions. Disclosures None. Sources of funding This reserch ws supported by internl funds only. Finncil support nd sponsorship Nil. Conflicts of interest There re no conflicts of interest. REFERENCES 1. Executive Committee for the Asymptomtic Crotid Atherosclerosis Study. Endrterectomy for symptomtic crotid rtery stenosis. JAMA 1995;273: AbuRhm AF, Srivstv M, Stone PA, Richmond BK, AbuRhm Z, Jckson W, et l. Effect of sttins on erly nd lte clinicl outcomes of crotid endrterectomy nd the rte of post crotid endrterectomy restenosis. J Am Coll Surg 2015;220: Agtston AS, Jnowitz WR, Hildner FJ, Zusmer NR, Vimonte M Jr, Detrno R. Quntifiction of coronry rtery clcium using ultrfst computed tomogrphy. J Am Coll Crdiol 1990;15: Arquizn C, Trinqurt L, Touboul PJ, Long A, Fesson S, Territ B, et l. EVA 3S Investigtors. Restenosis is more frequent fter crotid stenting thn fter endrterectomy: The EVA 3S study. Stroke 2011;42: Brros P, Felgueirs H, Pinheiro D, Guerr M, Gm V, Veloso M. Restenosis fter crotid rtery stenting using specific designed ultrsonogrphic protocol. J Stroke Cerebrovsc Dis 2014;23: Collbortors NASCET. Beneficil effect of crotid endrterectomy in symptomtic ptients with high grde crotid stenosis. N Engl J Med 1991;325: Cosottini M, Michelssi MC, Bencivelli W, Lzzrotti G, Picchietti S, Orlndi G, et l. In stent restenosis predictors fter crotid rtery stenting. Stroke Res Tret 2010;2010: Di Z, Xue G. Restenosis fter crotid rtery stenting. Vsculr 2017 [Epub hed of print]. 9. Dou B, Chlouhi N, Strke RM, Dlyi R, Polifk A, Srkr K, et l. Predictors of restenosis fter crotid rtery stenting in 241 cses. J Neurointerv Surg 2016;8: de Donto G, Setcci C, Deloose K, Peeters P, Cremonesi A, Bosiers M. Long term results of crotid rtery stenting. J Vsc Surg 2008;48: Fnous AA, Ntrjn SK, Jowdy PK, Dumont TM, Mokin M, Yu J, et l. High risk fctors in symptomtic ptients undergoing crotid rtery stenting with distl protection: Bufflo Risk Assessment Scle (BRASS). Neurosurgery 2015;77: Gry Wele AC, Grhm JC, Burnett JR, Byrne K, Lusby RJ. Crotid rtery therom: Comprison of preopertive B mode ultrsound ppernce with crotid endrterectomy specimen pthology. J Crdiovsc Surg (Torino) 1988;29: Hshimur N, Mutoh T, Mtsud K, Mtsumoto K. Evlution nd mngement of plque protrusion or thrombus following crotid rtery stenting. Neurol Med Chir (Tokyo) 2015;55: Indolfi C, Ciopp A, Stbile E, Di Lorenzo E, Esposito G, Pisni A, et l. Effects of hydroxymethylglutryl coenzyme A reductse inhibitor simvsttin on smooth muscle cell prolifertion in vitro nd neointiml formtion in vivo fter vsculr injury. J Am Coll Crdiol 2000;35: Ktno H, Mse M, Nishikw Y, Ymd H, Ymd K. Anlysis of recurrent stenosis fter crotid endrterectomy feturing primry plque clcifiction. Neurosurgery 2017;80: Ktno H, Mse M, Nishikw Y, Ymd K. Clcified crotid plques show double symptomtic peks ccording to Agtston clcium score. J Stroke Cerebrovsc Dis 2015;24: Ktno H, Mse M, Nishikw Y, Ymd K. Surgicl tretment for crotid stenoses with highly clcified plques. J Stroke Cerebrovsc Dis 2014;23: Ktno H, Ymd K. Anlysis of clcium in crotid plques with Agtston scores for pproprite selection of surgicl intervention. Stroke 2007;38: Ktno H, Ymd K. Crotid endrterectomy for stenoses of twisted crotid bifurctions. World Neurosurg 2010;73: Kotsugi M, Tkym K, Myouchin K, Wd T, Nkgw I, Nkgw H, et l. Crotid rtery stenting: Investigtion of plque protrusion incidence nd prognosis. JACC Crdiovsc Interv 2017;10: Kwon BJ, Jung C, Sheen SH, Cho JH, Hn MH. CT ngiogrphy of stented crotid rteries: Comprison with Doppler ultrsonogrphy. J Endovsc Ther 2007;14: Ll BK, Bech KW, Roubin GS, Lutsep HL, Moore WS, Mls MB, et l., CREST Investigtors. Restenosis fter crotid rtery stenting nd endrterectomy: A secondry nlysis of CREST, rndomised controlled tril. Lncet Neurol 2012;11: Leo HB, Jörg E, Dominick JH McCbe, Jonn D, Fetherstone RL, Gines PA, et l. Long term risk of crotid restenosis in ptients rndomly ssigned to endovsculr tretment or endrterectomy in the Crotid nd Vertebrl Artery Trnsluminl Angioplsty Study (CAVATAS): Long term follow up of rndomised tril. Lncet Neurol 2009;8: Mtsumoto H, Yko R, Msuo O, Hirym K, Uemtsu Y, Nko N. A Cse of In Stent Neotherosclerosis 10 Yers fter Crotid Artery Stent Implnttion: Observtion with Opticl Coherence Tomogrphy nd Plque Histologicl Findings. Neurol Med Chir (Tokyo) 2014;54: Miski K, Uchiym N, Mohri M, Hyshi Y, Ued F, Nkd M. Prediction of crotid rtery in stent restenosis by quntittive ssessment of vulnerble plque using computed tomogrphy. J Neurordiol 2016;43: Miyzki Y, Mori T, Iwt T, Aoygi Y, Tnno Y, Kskur S, et l. Continuous dily use of cilostzol prevents in stent restenosis following crotid rtery stenting: Seril ngiogrphic investigtion of 229 lesions. J Neurointerv Surg 2016;8: Moon K, Albuquerque FC, Levitt MR, Ahmed AS, Klni MY, McDougll CG. The myth of restenosis fter crotid ngioplsty nd stenting. J Neurointerv Surg 2016;8: Motoym S, Kondo T, Sri M, Sugiur A, Hrigy H, Sto T, et l. Multislice computed tomogrphic chrcteristics of coronry lesions in cute coronry syndromes. J Am Coll Crdiol 2007;50: Okhr M, Kiyosue H, Kshiwgi J, Ued S, Hori Y, Mori H. Smll in stent low density on CT ngiogrphy fter crotid rtery stenting. Interv Neurordiol 2008;14(Suppl 2): Ronchey S, Prquin B, Orrico M, Serro E, Ciceroni C, Alberti V, et l. Outcomes of 1000 crotid wllstent implnttions: Single center experience. J Endovsc Ther 2016;23: Shnkr JJ, Zhng J, dos Sntos M, Lesiuk H, Mohn R, Lum C. Fctors ffecting long term restenosis fter crotid stenting for crotid therosclerotic disese. Neurordiology 2012;54: Shinozki N, Ogt N, Ikri Y. Plque protrusion detected by intrvsculr ultrsound during crotid rtery stenting. J Stroke Cerebrovsc Dis 2014;23:

9 33. Sun ZS, Zhou SH, Gun X. Impct of blood circultion on reendotheliliztion, restenosis nd trovsttin s restenosis prevention effects. Int J Crdiol 2008;128: Tkigw T, Mtsumru Y, Hykw M, Nemoto S, Mtsumur A. Cilostzol reduces restenosis fter crotid rtery stenting. J Vsc Surg 2010;51: Tokung K, Kog M, Yoshimur S, Arihiro S, Suzuki R, Ngtsuk K, et l. Optiml pek systolic velocity thresholds for predicting internl crotid rtery stenosis greter thn or equl to 50%, 60%, 70%, nd 80%. J Stroke Cerebrovsc Dis 2016;25: Wsser K, Krch A, Gröschel S, Witzenhusen J, Gröschel K, Bähr M, et l. Plque morphology detected with Duplex ultrsound before crotid ngioplsty nd stenting (CAS) is not predictor of crotid rtery in stent restenosis, cse control study. BMC Neurol 2013;13: Wsser K, Schnudigel S, Wohlfhrt J, Psychogios MN, Knuth M, Gröschel K. Inflmmtion nd in stent restenosis: The role of serum mrkers nd stent chrcteristics in crotid rtery stenting. PloS One 2011;6:e Ydv JS, Wholey MH, Kuntz RE, Fyd P, Ktzen BT, Mishkel GJ, et l. Stenting nd Angioplsty with Protection in Ptients t High Risk for Endrterectomy Investigtors. Protected crotid rtery stenting versus endrterectomy in high risk ptients. N Engl J Med 2004;351: Ymgmi H, Ski N, Mtsumru Y, Ski C, Ki Y, Sugiu K, et l. Periprocedurl cilostzol tretment nd restenosis fter crotid rtery stenting: The Retrospective Study of In Stent Restenosis fter Crotid Artery Stenting (ReSISteR CAS). J Stroke Cerebrovsc Dis 2012;21: Zpt Arriz E, Moniche F, González A, Bustmnte A, Escudero Mrtínez I, De l Torre Lvin FJ, et l. Predictors of restenosis following crotid ngioplsty nd stenting. Stroke 2016;47: